# NM_000059.4(BRCA2):c.7759C>T (p.Leu2587Phe)

https://sugi.bio/variant/brca2-p-leu2587phe

## Summary

**BRCA2 p.Leu2587Phe (c.7759C>T)** is classified **Benign** in BRCA2 (ClinVar, Expert panel, 20 submitters; last evaluated 2025-05-23). AlphaMissense: ambiguous (0.5009); Very rare (popmax 0.00568%, nfe); Associated with BRCA2-related cancer predisposition.

**At a glance:** Benign · review: Expert panel · rsID rs56335340 · 20 submitters · 5 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00568%, nfe)

## For patients & families {#patients}

This is a change in the BRCA2 gene that is classified as benign — not considered disease-causing, submitted by 20 submitters, and is linked to BRCA2-related cancer predisposition.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026409/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BRCA2](https://sugi.bio/atlas/gene/BRCA2/) |
| Protein change (HGVS p.) | p.Leu2587Phe |
| Coding change (HGVS c.) | c.7759C>T |
| MANE Select transcript | [NM_000059](https://www.ncbi.nlm.nih.gov/nuccore/NM_000059) |
| dbSNP | [rs56335340](https://www.ncbi.nlm.nih.gov/snp/rs56335340/) |
| Variant type | single nucleotide variant |
| Location | chr13:32357883-32357883 (GRCh38) |
| ClinVar | [VCV141335](https://www.ncbi.nlm.nih.gov/clinvar/variation/141335/) |

**All HGVS expressions:** `LRG_293:g.47404C>T`, `LRG_293t1:c.7759C>T`, `NC_000013.10:g.32932020C>T`, `NC_000013.11:g.32357883C>T`, `NG_012772.3:g.47404C>T`, `NM_000059.4:c.7759C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5009) — no call either way
- REVEL 0.73 (pathogenic-leaning)
- Conservation: phyloP 4.82, GERP 1.16, phastCons 1 — highly conserved
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in BRCA2 (of 20,162 modeled).
- CADD: **PHRED 24.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.03** across the covering region of the MANE Select transcript (32,316,461–32,363,509), spanning 47,048 bp. Chi-square p 0.059. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00568%** (nfe) · FAF95 0.00453% · FAF99 0.00417% · 67/1,180,010 in the highest group · 75/1,613,928 alleles overall — very rare (popmax 0.00568%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,496 |
| European (non-Finnish) (grpmax) | 0.00568% | 17,612 |
| Admixed American | 0.00333% | 29,998 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,016 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BRCA2** population constraint: LOEUF 0.803, pLI 6.5274e-44, missense-Z 1.0218; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Fanconi anemia complementation group D1** — Definitive (AR)
- **BRCA2-related cancer predisposition** — Definitive (AD)

## Protein context {#protein}

Residue **2587** lies in the 'interaction with sem1' region.

**14 experimental structure(s)** (PDB): [1N0W](https://www.rcsb.org/structure/1N0W), [3EU7](https://www.rcsb.org/structure/3EU7), [6GY2](https://www.rcsb.org/structure/6GY2), [6HQU](https://www.rcsb.org/structure/6HQU), [7BDX](https://www.rcsb.org/structure/7BDX), [7LDG](https://www.rcsb.org/structure/7LDG) — incl. mutant structure 6HQU.

## What this gene does {#gene-function}

*Describes the biological roles of BRCA2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BRCA2's established molecular role includes protease binding. p.Leu2587Phe falls in the interaction with sem1 region. In Reactome, BRCA2 is annotated in disease pathway(s) including **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function**, **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function**.

**Disease mechanism (Reactome):** BRCA2 loss or alteration is curated in [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646), [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192).

### Pathways affected {#pathways}

BRCA2 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | curated |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | curated |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | curated |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | curated |
| ⚕ [Impaired BRCA2 binding to SEM1 (DSS1)](https://reactome.org/content/detail/R-HSA-9763198) | curated |
| ⚕ [Impaired BRCA2 translocation to the nucleus](https://reactome.org/content/detail/R-HSA-9709275) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through MMEJ (alt-NHEJ)](https://reactome.org/content/detail/R-HSA-5685939) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protease binding, single-stranded DNA binding, histone H3 acetyltransferase activity, histone H4 acetyltransferase activity, identical protein binding, gamma-tubulin binding.

**Biological process:** double-strand break repair via homologous recombination, nucleotide-excision repair, double-strand break repair, negative regulation of mammary gland epithelial cell proliferation, positive regulation of DNA-templated transcription, centrosome duplication.

## Clinical significance {#significance}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-05-23.

**Submitter consensus:** conflicting (9 Uncertain significance, 6 Likely benign, 3 Benign, 1 Likely Benign, 1 Likely pathogenic).

**Submission history:** 20 submissions (2015–2026); classifications have differed over time.

**ClinGen expert panel:** Benign — ENIGMA BRCA1 and BRCA2 VCEP (BRCA2-related cancer predisposition). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS3`, `BP4`, `BS1_Supporting`, `BP5_Standalone`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.7759C>T variant in BRCA2 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 2587 (p.Leu2587Phe). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.00004512 in the European (non-Finnish) population which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.15, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. A SpliceAI score of 0.04 predicts no impact on splicing (score threshold <0.10) (BP4 met).  Reported by four calibrated studies to exhibit protein function similar to benign control variants (PMIDs:38417439, 33293522, 39779857, 39779848) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.0022 (based on Cosegregation LR=0.092; Pathology LR=0.675; Family History LR=0.0345), below the thresholds for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID 34597585, 31853058).  In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS1_Supporting, BP4, BS3, BP5_Very strong).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50087 · approved 2025-05-23 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/f5cdac22-eb4f-453b-9e3f-a1d351529c9d).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-12-31 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Likely benign | criteria provided, single submitter | clinical testing | 2023-03-15 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-27 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2015-12-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-26 |
| Sema4, Sema4 | Uncertain significance | criteria provided, single submitter | curation | 2022-02-10 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-02-25 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-06-08 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2024-09-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-07 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-07-28 |
| True Health Diagnostics | Uncertain significance | no assertion criteria provided | clinical testing | 2018-04-06 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-05-21 |
| National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Benign | criteria provided, single submitter | clinical testing | 2021-11-16 |
| Department of Medical and Surgical Sciences, University of Bologna | Benign | no assertion criteria provided | clinical testing | 2023-09-01 |
| BRCAlab, Lund University | Uncertain significance | no assertion criteria provided | clinical testing | 2020-03-02 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-02-08 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Genetic Predisposition to Colorectal Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer | Likely pathogenic | criteria provided, single submitter | clinical testing | 2015-11-01 |
| ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Benign | reviewed by expert panel | curation | 2025-05-23 |

## Associated conditions {#conditions}

[BRCA2-related cancer predisposition](https://sugi.bio/atlas/disease/brca2-related-cancer-predisposition/), [colon carcinoma](https://sugi.bio/atlas/disease/colon-carcinoma/), [hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/), [breast-ovarian cancer, familial, susceptibility to, 2](https://sugi.bio/atlas/disease/breast-ovarian-cancer-familial-susceptibility-to-2/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** BRCA2-related cancer predisposition, Hereditary cancer-predisposing syndrome, not specified, Hereditary breast ovarian cancer syndrome, Breast-ovarian cancer, familial, susceptibility to, 2, Carcinoma of colon, not provided, BRCA2-related disorder, BRCA2-related condition, BRCA2-related disorders.

## Same-residue context {#hotspot}

Residue **2587** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BRCA2 p.Leu2587fs](/variant/brca2-p-leu2587fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRCA2 variant pages (same residue, condition, or type): [BRCA2 p.Leu2587=](/variant/brca2-p-leu2587), [BRCA2 p.Leu2587His](/variant/brca2-p-leu2587his), [BRCA2 p.Leu2587Pro](/variant/brca2-p-leu2587pro), [BRCA2 p.Leu2587fs](/variant/brca2-p-leu2587fs), [BRCA2 c.316+1G>T](/variant/brca2-c-316-plus-1g-t), [BRCA2 c.316+2T>C](/variant/brca2-c-316-plus-2t-c), [BRCA2 c.316+5G>A](/variant/brca2-c-316-plus-5g-a), [BRCA2 c.316+5G>C](/variant/brca2-c-316-plus-5g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 141335). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*